Out-smarting smart drug modafinil through flow chemistry

Abstract

Modafinil is an anti-narcoleptic drug used to treat excessive daytime sleepiness associated with sleep apnea and shift-work disorder. It is unique in its lack of significant side-effects or addiction-inducing properties and is currently utilized as a superior alternative to other options (e.g., amphetamines). Since the original report of its synthesis in 1976, nearly 20 manuscripts and patents have been published that propose alternative synthetic routes that limit the formation of problematic impurities, reduce the number of steps, or improve the green metrics of the process. Herein we show how the synthesis of modafinil can be improved in a continuous flow setup to deliver modafinil in 77% yield over three steps. No intermediate purification steps are required to obtain an output stream with modafinil in over 80% purity from which USP-grade modafinil can be isolated by precipitation, filtration and washing with solvent. The synthesis, performed entirely in class 3 FDA solvents, has a lower E-factor than current industrial processes and results entirely in innocuous side products (NaCl, NaHSO₄). Finally, the process can be conducted in a single concatenated flow setup and is the first step in our efforts towards constructing an end-to-end pharmaceutical manufacturing system.